Methotrexate is a well-known anti-cancer drug useful in the treatment of various forms of cancer. The process of the present invention is expected to considerably simplify the existing processes resulting in higher productivity and reduced costs.
The present invention is an improved process over the present commercial processes for the preparation of methotrexate such as the dibromopropionaldehyde process. It is considerably simpler, requires no extraordinary control to avoid loss of yield and produces methotrexate of high purity in a moderately high yield. A number of reactants needed in the dibromopropionaldehyde process have been eliminated.
The dibromopropionaldehyde process produces dihydromethotrexate which must be oxidized in situ with an oxidizing agent such as potassium triiodide. This oxidation step is extremely sensitive and must be appropriately controlled otherwise yields of methotrexate are substantially reduced. In contrast, the process of the present invention produces methotrexate directly and the process is easy to control. Purification is achieved via the insoluble zinc salt and crystallization of the sodium salt. The process results in high purity 98+% methotrexate.
The following patents and publications are presented herein to further develop the background of the present invention and establish the state of the existing art.
J.A.C.S. 71 1753-1758 (1949) discloses the preparation of methotrexate using 2,4,5,6-tetraaminopyrimidine sulfate, 2,3-dibromopropionaldehyde, p-(N-methylamino)-benzoylglutamic acid and barium chloride; and the preparation of aminopterin using 2,4,5,6-tetraaminopyrimidine sulfate, 1,1,3-tribromoacetone, p-aminobenzoyl-L(+)-glutamic acid and barium chloride.
C.A. 70 106833j (1970) discloses the preparation of methotrexate using tetraaminopyrimidine, trichloroacetone, and the barium salt of (N-methylamino)-benzoylglutamic acid.
U.S. Pat. No. 2,443,165 discloses a process for preparing pterins by reacting 2,4,5-triamino-6-hydroxypyrmidine with a trihaloacetone and aminobenzoic acid or one of its amides.
U.S. Pat. No. 2,512,572 describes the preparation of substituted pterins by simultaneously reacting a disubstituted 4,5-diaminopyrimidine, a dihaloproprionaldehyde, and a secondary amine.
U.S. Pat. No. 2,956,957; U.S. Pat. No. 2,719,157; and U.S. Pat. No. 2,443,165 disclose the reaction of various halo-substituted aldehydes and ketones, including 1,1,3-trichloro and 1,1,3-tribromoacetone with 2,4,5-triamino-6-hydroxypyrimidine, and p-aminobenzoyl glutamic acid to obtain folic acid.
U.S. Pat. No. 3,892,801 discloses the preparation of the zinc salt of p-aminobenzoylglutamic acid in preparation of the alkali metal salt of p-methylaminobenzoylglutamic acid used as an intermediate in the synthesis of methotrexate.
U.S. Pat. No. 4,136,101 discloses the preparation of diethyl N-(p-methylaminobenzoyl)glutamate, useful as an intermediate in the preparation of methotrexate, using zinc N-(p-methylaminobenzoyl)glutamate.